All multicellular organisms need mechanisms for immune recognition, to identify and combat external dangers such as pathogens. The innate immune system protects the host against infection, by eliminating pathogens while sustaining symbiosis with commensals. Innate immunity relies on inflammation to execute the antimicrobial defence, but the response must be carefully balanced, as destructive and protective outcomes may be closely related, and the innate immune response can be a cause of tissue dysfunction and disease. Molecular decisions that distinguish these facets of the immune response are poorly understood, however, which complicates the development of therapies aimed at boosting innate immunity.
Transcription factors regulate the magnitude and flavor of innate immune responses. Transcriptional control of the innate immune response is closely linked to inflammation and antimicrobial effector functions. Innate immunity is also regulated post-transcriptionally and by non-coding RNAs. Interferon regulatory factors (IRFs) control essential aspects of innate and specific immunity. IRF-7, originally identified in the context of Epstein-Barr virus infection, regulates type I interferons (IFNs) and anti-viral responses. In monocytic cells, IRF-3 and IRF-7 form heterodimers and the ratio plays an essential role for the inducible expression of type I IFN genes. Phosphorylated IRF-7 binds together with IRF-3 and NF-κB to virus-responsive IFN-α/β promoter elements and induces low amounts of type I IFNs, which bind to IFNARs and enhance IFN-dependent gene expression.
However, accelerating antibiotic resistance poses a major threat to human health, worldwide. Immunotherapies are therefore emerging as important alternatives to boost the host defense. Immune activation comes with a cost, however, as protective and destructive facets often are activated in concert. There is an obvious need to develop more selective therapies that boost the host defense and prevent pathology. A prerequisite for such developments is to define molecular tools to selectively target destructive inflammation. The applicants studied the effects of transcription factors as they determine the flavor of the innate immune response and in addition to the expression of individual genes.